Endometrial cancer is the most common gynecologic malignancy in the United States, with over 36,000 new cases diagnosed each year. A substantial fraction of these tumors arise on a background of endometrial hyperplasia. Two major risk factors for the development of endometrial hyperplasia and carcinoma have been identified, one of which is genetic and the other environmental. An inherited defect in DNA mismatch repair confers a approximately 50% lifetime risk for the development of endometrial carcinoma. Estrogens (both exogenous and endogenous) increase a woman's risk for the development of endometrial hyperplasia and cancer. We and others have demonstrated that somatic (acquired) defects in mismatch repair are frequent in endometrial cancer, further emphasizing the importance of loss of DNA mismatch repair in these tumors. The synthetic estrogen, diethylstilbestrol (DES), has been shown to induce reproductive tract malignancies in humans and mice. At this time, however, little is known about how estrogenic stimulation and loss of mismatch repair interact in endometrial tumorigenesis. We propose to define the roles that DNA mismatch repair and DES play in endometrial tumorigenesis through investigation of a mouse model. Mice that are +/+, +/- and -/- for a Mlh1 knockout allele will be exposed to the synthetic estrogen, DES. The age-specific penetrance and expressivity of DES-induced reproductive tract abnormalities will be determined for the three different genotypes. The cellular phenotypes will be described histologically and at the molecular level. Expression array studies will be used to define genetic signatures (transcriptomes) for the normal endometrium, endometrial hyperplasia and frank carcinoma. Comparison of the global changes in gene expression in cancers and precancerous lesions will provide insights into the genetic changes that are associated with phenotypic progression. Furthermore, comparison of DES-promoted cancers lacking mismatch repair with those that have normal DNA mismatch repair will point to pathways that are disrupted in mismatch repair deficient cancers. The results of these studies will provide the basis for future experiments into the molecular mechanisms by which estrogens and loss of mismatch repair contribute to endometrial tumor formation. The improved understanding of the molecular basis of uterine endometrial tumorigenesis will provide avenues for the prevention, detection and treatment of these malignancies and other hormonally promoted and responsive cancers.